This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Thyroid hormonogenesis requires iodide uptake and release into the thyroid follicular lumen. The apical exit of iodide is thought to be mediated by Pendrin, an anion exchanger encoded by the SLC26A4 gene. Patients with mutations in the SLC26A4 gene occasionally present with goiter, but in many cases are euthyroid. Moreover, a mouse Slc26a4 knockout shows no differences in thyroid hormone levels. These observations suggest that alternative pathways for apical iodide efflux exist in the thyroid gland. We have chosen to examine in greater detail the contributions of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) to luminal iodide accumulation. Polarized primary cultures were grown from wild type and CFTR -/- pig thyroids to facilitate evaluations of anion transport using short-circuit current (Isc) measurements as well as iodide flux measurements. Isc studies indicate the presence of cAMP-activated anion (chloride and iodide) secretion that is abolished in CFTR-/- pig thyroid cultures. Several possibilities are consistent with our findings to date. The first model tests whether CFTR directly mediates iodide efflux from thyroid follicular cell space and into the follicular lumen. The second model addresses whether CFTR-regulated Pendrin activity mediates iodide efflux. Taken together, it is possible that deficiency of either CFTR- or Pendrin produces suboptimal but sufficient thyroid function, whereas lack of both will engender detectable thyroid dysfunction.